Oral clefts represent one of the most common congenital malformations, (occurring with birth prevalences between 1 and 2 per thousand). Despite extensive study, at both the epidemiologic and genetic levels, the etiology of oral clefts remains ill-defined. Studies have consistently shown strong familial aggregation of oral clefts, and Mendelian inheritance has been proposed. Recently, an association between risk to non-syndromic cleft lip +/- palate and a candidate gene (transforming growth factor a) has been described (Ardinger et al , 1989). A systematic search for effects of candidate genes is a logical extension of the current understanding of the genetics of oral clefts, and there are many such candidates (e.g. genes for growth factors and their receptors, genes for extracellular matrix proteins, homeobox genes, etc.). However, the design of such a study must also incorporate environmental risk factors, as there is evidence for a role of maternal exposures in the etiology of oral clefts. We propose: 1) to carry out an epidemiologic study of non-syndromic oral clefts simultaneously considering effects of candidate genes and environmental exposures. Cases for this study will come from a state wide survey of newborns with an oral cleft and 5 surgical treatment centers serving Maryland during the period 1993-1997. A population based sample of control infants will be drawn as a comparison group. An additional 250 cases and 250 controls from the Atlanta Birth Defects Risk Factor Surveillance Study will also be available, and parallel analyses will be done. Tests for potential risk factors will include standard maternal exposures, infant sex, etc., but will also consider effects of genotypes at candidate genes. Polymerase chain reaction (PCR) based methods will be used to type both case and control infants for markers at a series of candidate loci. 2) to carry out formal genetic analyses to identify the mode of inheritance of non-syndromic oral clefts and test for co-segregation with markers at these candidate loci in multiplex families.